WO2012016082A1 - Quinoline derivatives and melk inhibitors containing the same - Google Patents

Quinoline derivatives and melk inhibitors containing the same Download PDF

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Publication number
WO2012016082A1
WO2012016082A1 PCT/US2011/045792 US2011045792W WO2012016082A1 WO 2012016082 A1 WO2012016082 A1 WO 2012016082A1 US 2011045792 W US2011045792 W US 2011045792W WO 2012016082 A1 WO2012016082 A1 WO 2012016082A1
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Prior art keywords
quinolin
amino
methanone
chloro
optionally substituted
Prior art date
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PCT/US2011/045792
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English (en)
French (fr)
Inventor
Yo Matsuo
Shoji Hisada
Yusuke Nakamura
Feryan Ahmed
Raymond Huntley
Joel R. Walker
Helene Decornez
Original Assignee
Oncotherapy Science, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN201180047405.5A priority Critical patent/CN103153063B/zh
Priority to KR1020137005377A priority patent/KR101826382B1/ko
Application filed by Oncotherapy Science, Inc. filed Critical Oncotherapy Science, Inc.
Priority to JP2013523213A priority patent/JP5849303B2/ja
Priority to BR112013002182A priority patent/BR112013002182B8/pt
Priority to ES11813209.1T priority patent/ES2565627T3/es
Priority to EP11813209.1A priority patent/EP2597955B1/en
Priority to US13/813,134 priority patent/US9120749B2/en
Priority to AU2011282588A priority patent/AU2011282588B2/en
Priority to SG2013006903A priority patent/SG187633A1/en
Priority to DK11813209.1T priority patent/DK2597955T3/en
Priority to RU2013108865/04A priority patent/RU2582610C2/ru
Priority to MX2013001201A priority patent/MX342879B/es
Priority to CA2806332A priority patent/CA2806332C/en
Publication of WO2012016082A1 publication Critical patent/WO2012016082A1/en
Priority to IL223871A priority patent/IL223871A/en
Priority to HK13111710.1A priority patent/HK1184331A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a quinoline derivative for inhibiting MELK activity, a method for the preparation thereof, and a pharmaceutical composition containing the compound as an active ingredient.
  • MELK maternal embryonic leucine zipper kinase
  • MELK is up-regulated in several cancer cells, for example lung, bladder, lymphoma and cervical cancer cells (See WO2004/031413, WO2007/013665, and WO2006/085684, the disclosures of which are incorporated by reference herein).
  • Northern blot analysis on multiple human tissues and cancer cell lines demonstrated that MELK was over-expressed at a significantly high level in a great majority of breast cancers and cell lines, but was not expressed in normal vital organs (heart, liver, lung and kidney) (WO2006/016525).
  • siRNA suppression of MELK expression by siRNA was shown to significantly inhibit growth of human breast cancer cells. Accordingly, MELK is considered to be a suitable target for cancer therapy in the treatment of a wide array of cancer types.
  • the present inventors have endeavored to develop an effective inhibitor of MELK and have found that a compound can selectively inhibit the activity of MELK.
  • the present invention relates to the following ( 1 ) to (33).
  • R 1 represents
  • Ci-C 6 alkylsulfinyl an optionally substituted Ci-C 6 alkylsulfinyl
  • Ci-C alkylsulfonyl an optionally substituted Ci-C alkylsulfonyl, or
  • R and R are the same or different and represent
  • R 2 represents
  • R 6 and R 7 are the same or different and represent
  • n an integer of 0 to 6
  • R 5 and R 7 form with an adjacent nitrogen atom an optionally substituted heterocycl group
  • R represents
  • R 101 represents
  • Ci-C 6 alkylsulfonyl a Ci-C 6 alkylsulfonyl
  • R 5 represents
  • Ci-C 6 alkyl which may have a substituent group selected from Substituent Group A,
  • R and R are the same or different and represent
  • R 2 represents
  • R 6 and R 7 are the same or different and represent
  • Ci-C 6 alky which may have a substituent group selected from Substituent Group A,
  • -C 6 alkylenyl) which may be substituted with a hydroxy, a C 2 -C 7 alkanoylamino-(Ci-C alkylenyl), or
  • n an integer of 0 to 6
  • R 10 represents
  • R 3 represents
  • Ci-C 6 alkoxy which may have a substituent group selected from Substituent Group A,
  • R 4 represents
  • R 101 represents
  • substituents are one to three substituents each independently selected from the following Substituent Groups:
  • Substituent Group A a halogen, an aliphatic heterocyclic group,, an optionally substituted aliphatic heterocyclic-carbonyl which may be substituted with a Ci-C 6 alkyl (the Ci-C 6 alkyl has the same meaning as the aforementioned Ci-C 6 alkyl)
  • Ci-C 6 alkylamino (wherein, the Ci-C 6 alkyl may have a hydroxy as a substituent), a di(Ci-C 6 alkyl)amino, a diallylamino,
  • Ci-C alkylamino-(Ci-C 6 alkylenyl) (wherein, the Ci-C 6 alkyl may have a halogen as a substituent),
  • a di(Ci-C 6 alkyl)amino-(Ci-C6 alkylenyl) (wherein, either a C)-C 6 alkyl or a Ci-C 6 alkylenyl may have a hydroxy or a cyano as a substituent, and wherein hydrogen atom of C
  • an aliphatic heterocyclic group (wherein, the aliphatic heterocyclic group may have a Ci-C 6 alkyl, an amino, a hydroxy, a halogen, a di(Ci-C alkyl)amino, a CpC 6 alkylamino, or a
  • an aliphatic heterocyclic-(Ci-C6 alkylenyl) (wherein, the aliphatic heterocyclic may have a Ci-C 6 alkyl, an amino, a hydroxy, a C
  • an aliphatic heterocyclic-carbonyl (wherein, the aliphatic heterocyclic may have a C(-C 6 alkyl as a substituent),
  • an aliphatic heterocyclic-carbonylamino (wherein, the aliphatic heterocyclic may have a Ci-C 6 alkyl as a substituent),
  • an aliphatic heterocyclic-amino (wherein, the aliphatic heterocyclic may have a C
  • Ci-C 6 aminoalkylcarbonylamino a hydroxyphenyl
  • cycloalkyl may have an amino, a Q-C 6 alkylamino, or a
  • Ci-C 6 aminoalkyl as a substituent
  • R 1 is R ,A [R IA represents a cyano, a Ci-C 6 alkylsulfinyl, a C,-C 6 alkylsulfonyl, or -CO-R 5A (wherein, R 5A represents a Ci-C 6 alkyl or a C3-C 10 cycloalkyl)],
  • R 2 is R 2A ⁇ R 2A represents an optionally substituted aryl which may have a substituent group selected from Substituent Group C, an optionally substituted aromatic heterocyclic group which may have a substituent group selected from Substituent Group H, or -NR 6A R 7A [wherein, R 6A represents a hydrogen atom, and R 7A represents -(CH 2 ) n -R l0A (wherein, n represents an integer of 0 to 6, and R 10A represents an optionally substituted C 3 -Cio cycloalkyl which may have a substituent group selected from Substituent Group D, an optionally substituted aryl which may have a substituent group selected from Substituent Group E, an aliphatic heterocyclic group which may be substituted with a Ci-C 6 alkyl, or an aromatic heterocyclic group which may have a substituent group selected from Substituent Group I), or R 6A and R 7A form with an adjacent nitrogen
  • R 3 is R 3A (R 3A represents an optionally substituted aryl which may have a substituent group selected from Substituent Group G, or an optionally substituted aromatic heterocyclic group which may have a substituent group selected from Substituent Group H), and
  • R 4 is a hydrogen atom or a halogen and R 101 is a hydrogen atom.
  • R 1A represents
  • Ci-C 6 alkylsulfonyl a Ci-C 6 alkylsulfonyl
  • R 5A represents a Ci -C 6 alkyl, or a C3-C10 cycloalkyl
  • R 2A represents
  • R 6A represents a hydrogen atom
  • R 7A represents
  • n an integer of 0 to 6
  • R 10A represents
  • R 6A and R 7A form with an adjacent nitrogen atom an optionally substituted heterocyclic group which may have a substituent group selected from Substituent Group F],
  • R 3A represents
  • R 4A represents a hydrogen atom or a halogen
  • substituents C to 1 are one to three substituents each independently selected from the following Substituent Groups:
  • Substituent Group C a halogen, a hydroxy, a Ci-C 6 alkoxy, and a di(Ci-C 6 alkyl)amino;
  • Substituent Group D a hydroxy, a Ci-C 6 alkyl, a C i-C 6 aminoalkyl, an aliphatic
  • heterocyclic-(Ci-C alkylenyl) (wherein, the aliphatic heterocyclic may have an amino, a hydroxy, a Ci-C 6 hydroxyalkyl, a C1-C6 alkoxy, or a halogen as a substituent), a Ci-C 6 alkylamino-(C
  • Substituent Group E a halogen, a di(Ci-C 6 alkyl)amino-(C
  • Substituent Group F a carbamoyl, an amino, a Ci-C 6 aminoalkyl, a di(Ci-C 6
  • alkyl amino-(Ci-C 6 alkylenyl), a C,-C 6 alkylamino-(Ci-C 6 alkylenyl), an aliphatic heterocyclic-(Ci-C 6 alkylenyl), and an aliphatic heterocyclic group which may be substituted with a C]-C 6 alkyl;
  • Substituent Group G a halogen, a hydroxy, a cyano, a Ci-C 6 alkyl, a C1 -C6 alkoxy, a trifluoromethoxy, a C)-C 6 aminoalkyl, a Ci-C 6 alkylamino-(C] -C 6 alkylenyl), a di(C
  • Substituent Group H a halogen, a cyano, a C 1-C6 alkyl, a C
  • Substituent Group H a halogen, a cyano, a C]-C 6 alkyl, a Ci-C 6 alkoxy, an amino, a carbamoyl, a dimethylaminopropylaminocarbonyl, and an aminocyclohexylaminocarbonyl;
  • Substituent Group I an aliphatic heterocyclic group (wherein, the aliphatic heterocyclic group may have a Ci-C 6 alkyl, an amino group, or a C i-C 6 alkylamino as a substituent); an aliphatic heterocyclic-(Ci-C 6 alkyleny
  • R 1 is a Ci-C 6 alkylsulfonyl.
  • R 1A , R 3A , R 4A , R 6A , and R 7A have the same meaning as described above.
  • R 10A is a three- to eight-membered monocyclic aliphatic heterocyclic group comprising at least one nitrogen atom which may be substituted with a Ci -C 6 alkyl; a C3-C10 cycloalkyl which may have a substituent group selected from Substituent Group D; a phenyl which may have a substituent group selected from Substituent Group E; or an aromatic heterocyclic group which may have a substituent group selected from Substituent Group I, wherein the aromatic heterocyclic group is a pyridyl, a pyrimidinyl, or a pyrazolyl.
  • Substituent Group D a hydroxy, a Ci-C 6 alkyl, a Ci-C 6 aminoalkyl, an aliphatic heterocyclic-(Ci-C 6 alkylenyl) (wherein, the aliphatic heterocyclic may have an amino, a hydroxy, a Ci -C 6 hydroxyalkyl, a C
  • Substituent Group E a halogen, a di(Ci-C 6 alkyl)amino-(Ci-C 6 alkylenyl) (wherein, the Ci-C 6 alkylenyl may have a hydroxy as a substituent), an amino, a C 2 -C 7 alkanoylamino, a di(Ci-C 6 alkyl)amino, a Ci-C 6 aminoalkyl, and an aliphatic heterocyclic-(C]-C 6 alkylenyl) (wherein, the aliphatic heterocyclic may have a Ci-C alkyl as a substituent)
  • R 2 is a piperidin-4-spiro-3'-pyrrolidin-l -yl, a piperidino which may have a substituent group selected from substituent Fa, or a 1 -piperazinyl which may have a substituent group selected from substituent Fa
  • the substituent Fa is a substituent selected from the group' consisting of an amino, a di(Ci-C 6 alkyl)amino-(Ci-C 6 alkylenyl), a C
  • R 2 is an optionally substituted aryl which may have a substituent group selected from Substituent Group C.
  • R 3 is an optionally substituted aryl which may have a substituent group selected from Substituent Group G, or an optionally substituted aromatic heterocyclic group which may have a substituent group selected from Substituent Group H.
  • R 3 is an optionally substituted phenyl which may have a substituent group selected from Substituent Group G, or an optionally substituted aromatic heterocyclic group which may have a substituent group selected from Substituent Group H, wherein the aromatic heterocyclic group is selected from the group consisting of a thienyl, a pyrrolyl, an imidazolyl, an isoxazolyl, a pyridyl, a pyrimidinyl, a pyrazolyl, a l H-indazolyl, a benzimidazolyl, a [l ,2,4]triazolo[l ,5-a]pyridyl, or a pyrrolo[2,3-b]pyridyl.
  • R 3 is an optionally substituted phenyl which may have a substituent group selected from Substituent Group G, or an optionally substituted aromatic heterocyclic group which may have a substituent group selected from Substituent Group H, wherein the aromatic heterocyclic group is selected from the group consisting of a pyridyl, a thienyl, a pyrimidinyl, a benzimidazolyl, and a l H-indazolyl.
  • propane-1 ,3-diamine compound 14 N-(4-(6-chloro-3 -(4-chlorobenzoyl)quinolin -4-ylamino)phenyl)
  • compound 40 (6-chloro-4-(piperidin-3-ylamino) quinolin-3-yl)(cyclopropyl) methanone compound 41 : 4-chloro-l -(6-chloro-4-(piperidin -3-ylamino)quinolin-3-yl) butan-l -one compound 42 : (6-chloro-4-((3-(dimethylamino) propyl)(methyl)amino)quinolin
  • compound 72 ethyl 4-(3-aminopropylamino) -6-bromoquinoline-3-carboxylate compound 73 : ethyl 6-bromo-4-(2-(diethylamino) ethylamino)quinoline -3 -carboxylate compound 74 : ethyl 6-bromo-4- ((l -ethylpyrrolidin-2-yl) methylamino)quinoline-3- carboxylate
  • compound 30 ethyl 6-bromo-4-(3-carbamoylpiperidin- l-yl)quinoline-3-carboxylate compound 31 : ethyl 6-bromo-4-(4-carbamoylpiperidin- l -yl)quinoline-3-carboxylate compound 32 : 5-(4-((trans)-4-aminocyclohexylamino)-3- (cyclopropanecarbonyl)quinolin -6-yl)pyridin-2(l H)-one
  • compound 229 (4-((trans)-4-aminocyclohexylamino)-6- (3-methyl- l H-pyrazol-4-yl) quinol in-3-yl)(cyclopropyl) methanone compound 230 : (4-((trans)-4-aminocyclohexylamino)-6- (3,4-dimethoxyphenyl)quinolin -3-yl)(cyclopropyl)methanone
  • compound 254 cyclopropyI(6-(3,5-difluoro-4- hydroxyphenyl)-4-((trans)-4- (dimethylamino)cyclohexylamino) quinolin-3-yl)methanone compound 255 : (6-(3-chloro-4-hydroxy-5- methoxyphenyl)-4-((trans)-4-
  • compound 263 cyclopropyl(6-(3,5-dichloro-4- hydroxyphenyl)-4-((trans)-4- (dimethylamino)cyclohexylamino) quinolin-3-yl)methanone (6-(3-chloro-5-fluoro-4- hydroxyphenyl)-4-((trans)-4- (dimethylamino)cyclohexylamino) quinolin-3-yl)(cyclopropyl) methanone
  • compound 333 l -(4-(4-((trans)-4-aminocyclohexylamino)-3- isobutyrylquinolin-6-yl)phenyl) -3-methylurea compound 334 : (6-(3-chloro-4-hydroxy-5- methoxyphenyl)-4-(4- quinolin-3-yl)(cyclopropyl) methanone
  • quinolin-3-yl)methanone (6-(3 -chloro-5 -fl uoro-4- hydroxypheny l)-4-((trans)-4- (pyrrolidin-l -yl)cyclohexylamino) quinolin-3-yl)(cyclopropyl) methanone
  • compound 547 cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-(4-((dimethylamino)me thyl)phenylamino)-7-fluoroquinolin-3-yl)methanone compound 548 : (4-(6-(4-aminopiperidin-l -yl)pyridin-3-ylamino)-6-(3,5-dichloro-4-hydro xyphenyl)quinolin-3-yl)(cyclopropyl)methanone
  • compound 549 (4-(6-(4-aminopiperidin-l -yl)pyridin-3-ylamino)-6-(3,5-dichloro-4-hydro xyphenyl)quinolin-3-yl)(cyclopropyl)methanone hydrochloride compound 550 : (4-(6-(4-aminopiperidin-l -yl)pyridin-3-ylamino)-6-(3-chloro-4-hydroxy- 5-methoxyphenyl)quinolin-3-yl)(cyclopropyl)methanone
  • compound 552 cyclopropyl(6-(3,5-dichloro-4-hydroxyphenyl)-4-(4-((dimethylamino)me thyl)phenylamino)-8-fluoroquinolin-3-yl)methanone compound 553 : (4-(2-(4-aminopiperidin-l -yl)pyrimidin-5-ylamino)-6-(3-chloro-4-hydrox y-5-methoxyphenyl)quinolin-3-yl)(cyclopropyl)methanone
  • compound 555 (4-(l R,4R)-4-aminocyclohexylamino)-6-(3-chloro-5-fluoro-4-hydroxyph enyl)-8-fluoroquinolin-3-yl)(cyclopropyI)methanone compound 556 : (4-(6-(3-aminopiperidin-l -yl)pyridin-3-ylamino)-6-(3,5-dichloro-4-hydro xyphenyl)quinolin-3-yl)(cyclopropyl)methanone
  • compound 557 (4-(6-(4-aminopiperidin- 1 -yl)pyridin-3-ylamino)-6-(3-chloro-5-fluoro-4- hydroxyphenyl)quinolin-3-yl)(cyclopropyl)methanone l -(6-(3,5-dichloro-4-hydroxyphenyl)-4-(l R,4R)-4-(methylamino)cyclohe xylamino)quinolin-3-yl)ethanone

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Quinoline Compounds (AREA)
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JP2013523213A JP5849303B2 (ja) 2010-07-30 2011-07-28 キノリン誘導体および同一物を含むｍｅｌｋ阻害剤
KR1020137005377A KR101826382B1 (ko) 2010-07-30 2011-07-28 퀴놀린 유도체 및 이를 함유하는 ｍｅｌｋ 억제제
ES11813209.1T ES2565627T3 (es) 2010-07-30 2011-07-28 Derivados de quinolina e inhibidores de MELK que contienen los mismos
EP11813209.1A EP2597955B1 (en) 2010-07-30 2011-07-28 Quinoline derivatives and melk inhibitors containing the same
DK11813209.1T DK2597955T3 (en) 2010-07-30 2011-07-28 QUINOLINE DERIVATIVES AND MILK INHIBITORS CONTAINING THESE
CN201180047405.5A CN103153063B (zh) 2010-07-30 2011-07-28 喹啉衍生物及含有其的melk抑制剂
BR112013002182A BR112013002182B8 (pt) 2010-07-30 2011-07-28 Compostos derivados de quinolina, composição farmacêutica, inibidor de melk, agente modulador de expressão de melk, agente antitumor, agente terapêutico e/ou preventivo para uma doença que envolve a superexpressão de melk contendo os mesmos e uso dos referidos compostos
US13/813,134 US9120749B2 (en) 2010-07-30 2011-07-28 Quinoline derivatives and MELK inhibitors containing the same
RU2013108865/04A RU2582610C2 (ru) 2010-07-30 2011-07-28 Производные хинолина и содержащие их ингибиторы melk
MX2013001201A MX342879B (es) 2010-07-30 2011-07-28 Derivados de quinolina e inhibidores de cinasa de cremallera de leucina embrionica materna que los contienen.
CA2806332A CA2806332C (en) 2010-07-30 2011-07-28 Quinoline derivatives and melk inhibitors containing the same
IL223871A IL223871A (en) 2010-07-30 2012-12-25 Quinoline derivatives and milk inhibitors containing them
HK13111710.1A HK1184331A1 (zh) 2010-07-30 2013-10-17 喹啉衍生物與含此之 抑制劑

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